Many drugs exist which pass the blood brain barrier and are therefore suitable for the treatment of certain disorders of the central nervous system. However, a number of additional substances exist which are of potential clinical usefulness, but that do not pass through the blood brain barrier. It is therefore desirable to develop methods to deliver these drugs directly to the central nervous system.
The prior art discloses several attempts to deliver drugs to the central nervous system (CNS) in a continuous fashion. The most widely known device is the ALZET.TM. minipump, a reservoir-type system which can continuously deliver a solution containing a drug, for example, dopamine or a dopamine agonist, for up to four weeks. Delivery is through a canula which is chronically implanted into the CNS, as described by Hargraves, et al. Life Sci 40, 959-966 (1987); and Yebenes, et al. J Neural Transm [Supp] 27, 141-160 (1988)). Implantable pumps for delivery of substances to the CNS are described by R. E. Harbaugh et al. Neurosurgery, 23(6), 693-698 (1988).
There are several disadvantages to this approach, including the relatively short period of time with which substances can be delivered to the CNS, the relative instability of the drug in solution, and recent reports of toxic effects of this method to deliver drugs to the CNS (H. L. Vahlsing et al., Soc. for Neuroscience Abstracts 14, No. 331.6 (1988). In addition, concerns over safety for reservoir-based pump systems in the case of damage or malfunction has tempered enthusiasm for this technique.
It is therefore desirable to obtain a device which is capable of delivering substances to CNS in a continuous fashion for prolonged periods of time without the need to suspend the drug in solution. Over the past twenty years, oral sustained release formulations of such drugs as aspirin have gained popularity. However, these formulations do not achieve the constant plasma (and hence brain) levels of drugs, critical for the effective treatment of neurological or psychiatric disorders.
For these reasons, it is desirable to provide a non-oral or mechanical controlled drug release system for use in treating nervous system disorders. Despite the use of controlled drug delivery systems in the treatment of a variety of diseases, including malignancy, and metabolic defects such as diabetes, it has never been directly applied to the treatment of non-malignant nervous disorders, including ischemic, metabolic, congenital or degenerative disorders, wherein the purpose is to replace lost function or prevent defective function. This is despite the fact that the technology for encapsulating bioactive compounds within a polymeric device has been known for a long time and people have suggested that such devices might be useful for treatment of nervous disorders. There are a number of reasons why this technology has not been successfully reduced to practice, including the complexity of the nervous system, the difficulties in delivery of substances to the nervous system, especially the brain, and the differences in response of individual patients to drugs delivered locally at a constant rate and dosage rather than in discrete doses via the circulatory system. An example of a prior art polyanhydride drug delivery device is taught by U.S. Pat. No. 3,625,214 to Higuchi. This device consists of a spirally wound layer of biodegradable polymer overlaid with drug which is released as the polymer degrades. Although it is noted that a variety of configurations can be used to achieve a desired release pattern, there is no teaching of how to treat neural disorders where the goal is to replace or supplement the biological function of the cells, not just to introduce a substance having a particular effect when administered by conventional means.
The nervous system is complex and physically different from the rest of the body. There are two "systems", the central nervous system and the peripheral nervous system. As used in the present invention, "central nervous system" includes both the brain and spinal cord and "peripheral nervous system" includes the nerves, ganglia, and plexus. The peripheral nervous system is divided into the autonomic and somatic nerves. The somatic nerves innervate the skeletal muscles and the autonomic nerves supply the enervation to the heart, blood vessels, glands, other visceral organs, and smooth muscles. The motor nerves to the skeletal muscles are myelinated, whereas the postganglionic autonomic nerves are generally nonmyelinated. The autonomic nervous system is further divided into the sympathetic and the parasympathetic nerves. In general, the sympathetic and parasympathetic systems are viewed as physiological antagonists. However, the activities of the two on specific structures may be different and independent or integrated and interdependent.
As is readily apparent, both the physical differences and interrelatedness of these components of the nervous system must be taken into account in designing a drug delivery system. As stated in The Pharmacological Basis of Therapeutics, edited by Gilman et al, on page 10 (MacMillan Publishing Company, New York 1980) "The distribution of drugs to the CNS from the blood stream is unique, mainly in that entry of drugs into the CNS extracellular space and cerebrospinal fluid is restricted . . . . Endothelial cells of the brain capillaries differ from their counterparts in most tissues by the absence of intercellular pores and pinocytotic vesicles. Tight junctions predominate, and aqueous bulk flow is thus severely restricted . . . . The drug molecules probably must traverse not only endothelial but also perivascular cell membranes before reaching neurons or other drug target cells in the CNS . . . . In addition, organic ions are extruded from the cerebrospinal fluid into blood at the choroid plexus by transport processes similar to those in the renal tubule. Lipid-soluble substances leave the brain by diffusion through the capillaries and the blood-choroid plexus boundary. Drugs and endogenous metabolites, regardless of lipid solubility and molecular size, also exit with bulk flow of the cerebrospinal fluid through the arachnoid villi . . . . The blood-brain barrier is adaptive in that exclusion of drugs and other foreign agents such as penicillin or tubocurarine protects the CNS against severely toxic effects. However, the barrier is neither absolute nor invariable. Very large doses of penicillin may produce seizures; meningeal or encephalitic inflammation increases the local permeability."
There are other problems. The immune system does not function within the CNS in the same manner as it does in the tissues and corporeal systems. A representative example of the problems in treating nervous system disorders is in the treatment of bacterial meningitis with antibiotics. Very toxic and high concentrations of the drugs are required.
During the 1980s, more sophisticated drug delivery systems were designed to achieve a truly constant, or "controlled", release of either low or high molecular weight compounds. One such drug delivery system is a polymer matrix fabricated with ethylene-vinyl acetate (EVA). This matrix consists of a continuous phase of polymer carrier with a dispersed phase of drug powder particles. A delivery device containing dry drug particles, instead of drug in solution, is advantageous since the drug remains stable in dry form for significantly longer periods of time than in solution.
The mechanism of drug release from polymer matrix has been proposed to be as follows: as soon as the polymer is brought into contact with a physiological medium such as saline, the medium has access to the outer most particles of the water-soluble phase of the polymer, i.e. the drug particles at the surface of the matrix. The diffusion of the drug particles leaves behind pores in the polymer matrix through which the medium gains access to the next layer of drug particles. In this way, drug molecules continuously diffuse out through the previously emptied pores and their interconnecting channels into the aqueous environment. A number of fabrication factors influence the kinetics of drug release: drug-particle size, drug loading, matrix coating, and drug solubility.
As first demonstrated in U.S. Ser. No. 07/043,695 filed Apr. 29, 1987, U.S. Pat. No. 4,883,666, controlled-release polymers can be used for the delivery of substances to the CNS. Other investigators have subsequently confirmed that the use of controlled release is both efficacious and advantageous over other methods for delivery of drugs to the CNS. For example, McRae-Degueurce et al., Neuroscience Letters (Ireland) 92(3), 303-309 (1988), disclose an implantable microencapsulated dopamine device and Gonzalez et al., Abstracts of the Soc. Neuroscience, No. 353.15 (1988), disclose a dopamine secreting polymeric device. Although these demonstrated delivery to the CNS, neither showed controlled (zero-order) drug delivery to the CNS, nor extended term release. A method whereby a small controlled-delivery device implanted into the CNS was used to deliver vasopressin to the cerebrospinal fluid with zero-order kinetics was described by Boer, et al., J. Neuroscience Methods, 11, 281-289 (Elsevier: The Netherlands 1984), but zero-order release was not obtained for a period beyond one week.
In summary, only in U.S. Ser. No. 07/043,695, U.S. Pat. No. 4,883,666 has a method been disclosed whereby substances can be delivered to the CNS which is clinically practicable and safe and which is characterized by long-term controlled release kinetics. This type of release is particularly desirable as a treatment for a variety of CNS disorders since it allows targeting drugs to the brain without adverse side effects arising from variations in delivery.
An example of a disorder of the CNS which has been especially difficult to treat is Parkinson's disease. The treatment of Parkinson's Disease patients with the dopamine biosynthetic precursor L-DOPA (in conjunction with a decarboxylase inhibitor) is an effective approach for the reduction of extrapyramidal symptoms in Parkinson's disease and has enjoyed wide acceptance. Nevertheless, a number of problems still remain unresolved which are of concern, particularly to patients in advanced states of the disease.
Treatment of patients with Parkinson's disease is primarily by systemic administration of dopamine and dopamine agonists. In the first few years of the disease, the majority of Parkinson's patients show a clinically stable response to L-DOPA therapy despite fluctuations in plasma L-DOPA levels. However, after several years of oral L-DOPA therapy, the CNS progressively fails to smooth out amplitude swings of plasma (L-DOPA) into a sustained biological response and patients start fluctuating clinically. Symptom reduction, for example in motor performance ("on"-period), alternates, sometimes abruptly, with periods where L-DOPA treatment seems ineffective and symptoms reappear ("off"-period). The emergence of such clinical fluctuations are often referred to as the "wearing-off" effect and, with further progression of the disease, they become a serious problem for the patient.
In many patients, these fluctuations in clinical response appear to be synchronized with fluctuations in plasma levels of L-DOPA associated with the timing and dose of oral ingestion of L-DOPA in conjunction with some form of dopa-decarboxylase inhibitor (e.g. Sinemet or Madopar). This observation suggests that fluctuations in plasma levels of L-DOPA may be directly responsible for the unstable clinical response. In an attempt to alleviate this problem, studies have been conducted using various methods of slow delivery of L-DOPA or dopamine receptor agonists, including i.v.-infusion, implantable or external reservoir pump systems or oral slow release preparations, such as Sinemet CR 3 - CR 5 and Madopar HBS, as well as others. Although the application of i.v.-infusion or pump systems have optimal or near-optimal release kinetics, these approaches are unsatisfactory with respect to practicality or reliability.
In contrast, oral slow-release preparations are relatively practical and reliable, but kinetic studies show that they do not provide constant ("controlled") delivery but simply temporarily retard the release ("sustained"-release). This temporary sustained release is not only due to gastric emptying, but also due to the release kinetics of the oral preparation itself. Although oral slow-release preparations do appear to improve the condition of patients in some cases, in others they are ineffective or have even been reported in rare cases to be detrimental. Taken together with earlier i.v. infusion studies, these results nevertheless provide evidence that controlled delivery of L-DOPA is a superior treatment modality.
Another type of treatment which has been attempted is by brain tissue grafting. A permanent reduction of lesion-induced behavioral deficits has been achieved in animal models of Parkinson's disease using grafts of fetal dopaminergic brain tissue or autologous adrenal medullary tissue. These animal experiments have raised the enthusiastic hope of both scientists and the public alike that permanent functional restoration by tissue grafts may also be achieved in patients. This has prompted a vigorous effort to test the efficacy of the transplantation technique in human subjects. Despite earlier preliminary reports of successful clinical trials from Sweden and Mexico, enthusiastic appraisals have given way to a more realistic view, recognizing theoretical and practical problems associated with the brain grafting approach. Included among the problems still under discussion are questions asking whether the implantation of fetal brain tissue is indeed effective in patients, and acceptable from an ethical point of view.
It is therefore an object of the present invention to provide a method and compositions for treating disorders of the CNS, for example, Parkinson's disease, which eliminate the plasma drug level swings and clinical response fluctuations after oral systemic administration.